SUMMARY OF WORK Cardiac cell loss occurs in response to acute ischemic injury, during heart failure, and during the normal aging of the heart. Cell loss is due predominantly to the death of cardiac myocytes and is mediated in large part by apoptosis.We have shown that heartand skeletal muscle contain a specific inhibitor of caspases 2 and 8, known as ARC (Apoptosis repressor with CARD), and that ARC expression is dramatically reduced during ischemic stress both in cultured myocytes and the intact heart. Restoring ARC levels using recombinant adenoviruses completely prevents cell death, while direct and complete caspase inhibition provides only limited protection. Protection through ARC is associated with inhibition of caspase 2 activation and inhibition of cytochrome c release, which occurs in a caspase-independent manner. ARC also regulates NF-kB activity by altering the transcriptional activation domain of the p65/RelA component of NF-kB to promote survival. In cells that are terminally growth-arrested, such as heart cells, ARC expression is associated with increased termination differentiation and increased cellular size or hypertrophy. Forced expression of ARC promotes skeletal muscle muscle differentiation, an event that in H9c2 cells is accompanied by a transient shift in ARC's cellular localization to the nucleus. In hearts and heart cells, hypertrophy-inducing agents increase ARC expression and formed expression of ARC results in enlarged myocytes in culture and enlarged hearts in vivo. In many proliferating cells, ARC is a potent suppressor of cell proliferation. These results demonstrate novel and unexpected roles for thei apoptosis repressor, linked to its peculiar pattern of expression. ARC may provide the missing mechanistic link between cellular differentiation, proliferation, and sensitivity to apoptosis in the heart and skeletal muscle.